Novel substituted benzoxazines as integrin antagonists

ABSTRACT

The present invention relates to a class of compounds represented by the formula (I)  
                 
 
     or a pharmaceutical acceptable salt, prodrug or ester thereof, pharmaceutical compositions comprising compounds of the formula (I), and methods of selectively inhibiting or antagonizing α v β 3  integrin.

FIELD OF THE INVENTION

[0001] The present invention relates to novel compounds which bind tothe integrin receptor α_(v)β₃, to pharmaceutical compositions containingsuch compounds, processes for preparing such compounds, and to methodsof using these compounds, alone or in combination with other therapeuticagents.

BACKGROUND OF THE INVENTION

[0002] Integrins are a group of cell surface glycoproteins which mediatecell adhesion and therefore are useful mediators of cell adhesioninteractions which occur during various biological processes. Integrinsare heterodimers composed of noncovalently linked α and β polypeptidesubunits. Currently eleven different a subunits have been identified andsix different β subunits have been identified. The various α subunitscan combine with various β subunits to form distinct integrins.

[0003] The integrin identified as α_(v)β₃ (also known as the vitronectinreceptor) has been identified as an integrin which plays a role invarious conditions or disease states including tumor metastasis, solidtumor growth (neoplasia), osteoporosis, Paget's disease, humoralhypercalcemia of malignancy, angiogenesis, including tumor angiogenesis,retinopathy including macular degeneration, arthritis, includingrheumatoid arthritis, periodontal disease, psoriasis and smooth musclecell migration (e.g. restenosis artherosclerosis). Additionally, it hasbeen found that such agents would be useful as antivirals, antifungalsand antimicrobials. Thus, compounds which selectively inhibit orantagonize α_(v)β₃would be beneficial for treating such conditions.

[0004] It has been shown that the α_(v)β₃ integrin and other α_(v)containing integrins bind to a number of Arg-Gly-Asp (RGD) containingmatrix macromolecules. Compounds containing the RGD sequence mimicextracellular matrix ligands so as to bind to cell surface receptors.However, it is also known that RGD peptides in general are non-selectivefor RGD dependent integrins. For example, most RGD peptides which bindto α_(v)β₃ also bind to α_(v)β₅, α_(v)β₁ and α_(IIb)β₃. Antagonism ofplatelet α_(IIb)β₃ (also known as the fibrinogen receptor) is known toblock platelet aggregation in humans. In order to avoid bleedingside-effects when treating the conditions or disease states associatedwith the integrin α_(v)β₃, it would be beneficial to develop compoundswhich are selective antagonists of α_(v)β₃ as opposed to α_(IIb)β₃.

[0005] The compounds of this invention are therefore selective α_(v)β₃integrin antagonist. The present invention includes compounds whichinhibit the respective integrins and also includes pharmaceuticalcompositions comprising such compounds. The present invention furtherprovides for methods for treating or preventing conditions mediated bythe α_(v)β₃ receptor in a mammal in need of such treatment comprisingadministering a therapeutically effective amount of the compounds of thepresent invention and pharmaceutical compositions of the presentinvention. Administration of such compounds and compositions of thepresent invention inhibits angiogenesis, tumor metastasis, tumor growth,osteoporosis, Paget's disease, humoral hypercalcemia of malignancy,retinopathy, macular degeneration, arthritis, periodontal disease,smooth muscle cell migration, including restenosis and artherosclerosis,and viral diseases.

[0006] Tumor cell invasion occurs by a three step process: 1) tumor cellattachment to extracellular matrix; 2) proteolytic dissolution of thematrix; and 3) movement of the cells through the dissolved barrier. Thisprocess can occur repeatedly and can result in metastases at sitesdistant from the original tumor.

[0007] Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992)1557-1561) have shown that the α_(v)β₃ integrin has a biologicalfunction in melanoma cell invasion. Montgomery et al., (Proc. Natl.Acad. Sci. USA, Vol. 91 (1994) 8856-60) have demonstrated that theintegrin α_(v)β₃ expressed on human melanoma cells promotes a survivalsignal, protecting the cells from apoptosis. Mediation of the tumor cellmetastatic pathway by interference with the α_(v)β₃ integrin celladhesion receptor to impede tumor metastasis would be beneficial.

[0008] Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) have demonstratedthat antagonists of α_(v)β₃ provide a therapeutic approach for thetreatment of neoplasia (inhibition of solid tumor growth) since systemicadministration of α_(v)β₃ antagonists causes dramatic regression ofvarious histologically distinct human tumors.

[0009] The adhesion receptor integrin α_(v)β₃ was identified as a markerof angiogenic blood vessels in chick and man and therefore such receptorplays a critical role in angiogenesis or neovascularization.Angiogenesis is characterized by the invasion, migration andproliferation of smooth muscle and endothelial cells. Antagonists ofα_(v)β₃ inhibit this process by selectively promoting apoptosis of cellsin neovasculature. The growth of new blood vessels, or angiogenesis,also contributes to pathological conditions such as diabetic retinopathyincluding macular degeneration (Adamis et al., Amer. J. Ophthal., Vol.118, (1994) 445-450) and rheumatoid arthritis (Peacock et al., J. Exp.Med., Vol. 175, (1992), 1135-1138). Therefore, α_(v)β₃ antagonists wouldbe useful therapeutic agents for treating such conditions associatedwith neovascularization (Brooks et al., Science, Vol. 264, (1994),569-571).

[0010] It has been reported that the cell surface receptor α_(v)β₃ isthe major integrin on osteoclasts responsible for attachment to bone.Osteoclasts cause bone resorption and when such bone resorbing activityexceeds bone forming activity it results in osteoporosis (loss of bone),which leads to an increased number of bone fractures, incapacitation andincreased mortality. Antagonists of α_(v)β₃ have been shown to be potentinhibitors of osteoclastic activity both in vitro [Sato et al., J. Cell.Biol., Vol. 111 (1990) 1713-1723] and in vivo [Fisher et al.,Endocrinology, Vol. 132 (1993) 1411-1413]. Antagonism of α_(v)β₃ leadsto decreased bone resorption and therefore restores a normal balance ofbone forming and resorbing activity. Thus it would be beneficial toprovide antagonists of osteoclast α_(v)β₃ which are effective inhibitorsof bone resorption and therefore are useful in the treatment orprevention of osteoporosis.

[0011] The role of the α_(v)β₃ integrin in smooth muscle cell migrationalso makes it a therapeutic target for prevention or inhibition ofneointimal hyperplasia which is a leading cause of restenosis aftervascular procedures (Choi et al., J. Vasc. Surg. Vol. 19(1) (1994)125-34). Prevention or inhibition of neointimal hyperplasia bypharmaceutical agents to prevent or inhibit restenosis would bebeneficial.

[0012] White (Current Biology, Vol. 3(9)(1993) 596-599) has reportedthat adenovirus uses α_(v)β₃ for entering host cells. The integrinappears to be required for endocytosis of the virus particle and may berequired for penetration of the viral genome into the host cellcytoplasm. Thus compounds which inhibit α_(v)β₃ would find usefulness asantiviral agents.

SUMMARY OF THE INVENTION

[0013] The present invention as a first object provides novel compoundsof the following formula (I)

[0014] or a pharmaceutically acceptable salt, prodrug or ester thereof,wherein:

[0015] G is selected from the group consisting of

[0016] wherein Q is NH or O and Q′ is H, C₁-C₆ alkyl, phenyl, orphenyl-C₁-C₄-alkyl;

[0017] wherein R′ and R″ are independently H or C₁-C₄ alkyl;

[0018] B is (CH₂)_(m)(CH═CH)_(p)Y, wherein m=1,2,3, p=0,1, Y is CH₂ orCO.

[0019] X is CH₂ or C═O;

[0020] R1 is selected from the group consisting of H, C₁-C₄ alkyl, C₁-C₄alkoxy, OH, halogen, CF₃;

[0021] A is CH₂, NH, O, S(O), wherein n is zero, 1 or 2.

[0022] R2 is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl or C₅-C₇monocyclic heteroaryl ring containing one to three heteroatoms selectedfrom O, S, and N, unsubstituted or optionally substituted by one tothree substituents independently selected from H, C₁-C₄ alkyl, C₁-C₄alkoxy, OH, halogen, CF₃;

[0023] R is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₄ alkynyl, aryl oraryl-C₁-C₄ alkyl.

[0024] The present invention includes within its scope all possibleisomers, stereoisomers and optical isomers and their mixtures, thechemical and bioprecursors and metabolites of the compounds of formula(I).

[0025] It is another object of the invention to provide pharmaceuticalcompositions comprising compounds of the Formula I. Such compounds andcompositions are useful in selectively inhibiting or antagonizing theα_(v)β₃ integrin and therefore in another embodiment the presentinvention relates to a method of selectively inhibiting or antagonizingthe α_(v)β₃ integrin. The invention further involves treating orinhibiting pathological conditions associated therewith such asosteoporosis, humoral hypercalcemia of malignancy, Paget's disease,tumor metastasis, solid tumor growth (neoplasia), angiogenesis,including tumor angiogenesis, retinopathy including macular degenerationand diabetic retinopathy, arthritis, including rheumatoid arthritis,periodontal disease, psoriasis, smooth muscle cell migration andrestenosis in a mammal in need of such treatment. Additionally, suchpharmaceutical agents are useful as antiviral agents, andantimicrobials.

DETAILED DESCRIPTION

[0026] The present invention relates to a class of compounds representedby the Formula I, described above.

[0027] A halogen atom is preferably chlorine or fluorine.

[0028] The alkyl, alkoxy, alkenyl and alkynyl groups and the alkyleneand alkenylene chains may be branched or straight groups or chains,respectively.

[0029] An aryl group is, e.g., an aromatic C₆-C₂₀ mono- or poly-nuclearmoiety, typically phenyl, naphthyl, unsubstituted or substituted by oneto three substituents independently chosen from halogen, hydroxy, CF₃,C₁-C₄ alkyl and C₁-C₄ alkoxy.

[0030] A C₅-C₇ monocyclic heteroaryl ring is preferably a C₅-C₆heteromonocyclic ring, in particular selected from pyridine, pyrazine,pyridazine, pyrimidine, thiophene, pyrrole, pyrazole, imidazole, oxazoleand isoxazole.

[0031] Accordingly an aralkyl group is e.g. benzyl or phenethyl, inwhich the phenyl ring is optionally substituted by one to threesubstituents independently selected from halogen, hydroxy, CF₃, C₁-C₄alkyl and C₁-C₄ alkoxy.

[0032] A C₂-C₆ alkenyl group is preferably an allyl group.

[0033] A C₁-C₆ alkyl group is preferably a C₁-C₄ alkyl group.

[0034] A C₁-C₄ alkyl group is preferably a methyl or ethyl group.

[0035] A C₂-C₄ alkynyl group is preferably an ethynyl group.

[0036] A C₁-C₄ alkoxy group is preferably methoxy, ethoxy, propoxy orbutoxy.

[0037] Examples of pharmaceutically acceptable salts of the compounds ofthe invention are either those with inorganic bases, such as sodium,potassium, calcium and aluminum hydroxides, or with organic bases, suchas lysine, arginine, N-methyl-glucamine, triethylamine, triethanolamine,dibenzylamine, methylbenzylamine, di-(2-ethyl-hexyl)-amine, piperidine,N-ethylpiperidine, N,N-diethylaminoethylamine, N-ethylmorpholine,β-phenethylamine, N-benzyl-β-phenethylamine, N-benzyl-N,N-dimethylamineand the other acceptable organic amines, as well as the salts withinorganic acids, e.g. hydrochloric, hydrobromic and sulphuric acids andwith organic acids, e.g. citric, tartaric, maleic, malic, fumaric,trifluoroacetic, methanesulphonic and ethanesulphonic acids.

[0038] As stated above, the present invention also includes within itsscope pharmaceutically acceptable bio-precursors (otherwise known aspro-drugs) of the compounds of formula (I), i.e. compounds which have adifferent formula to formula (I) above, but which nevertheless uponadministration to a human being are converted directly or indirectly invivo into a compound of formula (I).

[0039] Preferred compounds of the invention are those, in formula (I),wherein R, R1, X and A are as defined above;

[0040] B is (CH₂)_(m)(CH═CH)_(p)Y, wherein m=1,2,3, p=0 and Y is CH₂;

[0041] R2 is a phenyl, naphthyl, pyridine, pyrazine, pyridazine,pyrimidine, thiophene, pyrrole, pyrazole, imidazole, oxazole andisoxazole unsubstituted or optionally substituted as defined above; andG is selected from the group consisting of

[0042] wherein Q is NH or O and Q′ is H, C₁-C₆ alkyl, phenyl, or phenyl-C₁-C₄-alkyl;

[0043] and the pharmaceutically acceptable salts, prodrugs and estersthereof.

[0044] Most preferred compounds of the invention are those wherein, informula (I), B, X, R1, A and R are as defined above

[0045] R2 is a phenyl, thiophene, oxazole, isoxazole, or a pyridine ringunsubstituted or optionally substituted as defined above; and G isselected from the group consisting of

[0046] and the pharmaceutically acceptable salts, prodrugs and estersthereof.

[0047] Examples of specific preferred compounds according to theinvention are the following:

[0048]3-phenyl-N-{4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;

[0049]3-phenyl-N-{4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;

[0050]3-phenyl-N-{4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;

[0051]N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;

[0052]N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;

[0053]N-{4-[2-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;

[0054]3-(3-pyridinyl)-N-{4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;

[0055]3-(3-pyridinyl)-N-{4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;

[0056]3-(3-pyridinyl)-N-{4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;

[0057]N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;

[0058]N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;

[0059]N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;

[0060]N-{3-oxo-4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;

[0061]N-{3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;

[0062]N-{3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;

[0063]N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;

[0064]N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;

[0065]N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;

[0066]N-{3-oxo-4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;

[0067]N-{3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;

[0068]N-{3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;

[0069]N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;

[0070]N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;

[0071]N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;

[0072]3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoicacid;

[0073]3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoicacid;

[0074]3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoicacid;

[0075]3-({3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoicacid;

[0076]3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoicacid;

[0077]3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoicacid;

[0078]3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(pyridinyl)propanoicacid;

[0079]3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoicacid;

[0080]3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoicacid;

[0081]3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoicacid;

[0082]3-({3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-ppyridinyl)propanoicacid;

[0083]3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoicacid;

[0084]3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoicacid;

[0085]3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoicacid;

[0086]4-{3-oxo-4-[4-(pyridin-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoicacid;

[0087]4-{3-oxo-4-[3-(1H-imidazol-2-ylamino)-propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoicacid;

[0088]4-{3-oxo-4-[4-(1H-imidazol-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoicacid;

[0089]4-{3-oxo-4-[4-(pyridin-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoicacid;

[0090]4-{3-oxo-4-[3-(1H-imidazol-2-ylamino)-propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoicacid;

[0091]4-{3-oxo-4-[4-(1H-imidazol-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoicacid;

[0092] A further object of the present invention is to provide acompound of formula (I) as defined above or a pharmaceuticallyacceptable salt, prodrug or ester thereof, for use in a method oftreatment of the human or animal body by therapy, in particular fortreating conditions mediated by the α_(v)β₃ integrin.

[0093] The object of the present invention is also to provide apharmaceutical composition comprising a pharmaceutically acceptablecarrier and/or diluent and as an active principle a compound of formula(I), as herein defined, or a pharmaceutically acceptable salt thereof.

[0094] The present invention also provides the use of a compound offormula (I), as defined above, in the preparation of a medicament havingα_(v)β₃ integrin inhibiting or antagonizing activity.

[0095] The present invention also provides a method for treatingconditions mediated by the α_(v)β₃ integrin in a mammal, includinghumans, in need of such treatment comprising administering to saidmammal an effective α_(v)β₃ inhibiting or antagonizing amount of acompound of formula (I) as defined above or a pharmaceuticallyacceptable salt thereof

[0096] More specifically, the present invention provides a method forinhibiting bone resorption, treating osteoporosis, inhibiting humoralhypercalcemia of malignancy, treating Paget's disease, inhibiting tumormetastasis, inhibiting neoplasia (solid tumor growth), inhibitingangiogenesis including tumor angiogenesis, treating diabeticretinopathy, inhibiting arthritis, psoriasis and periodontal disease,and inhibiting smooth muscle cell migration including restenosis.

[0097] The compounds of the invention and the salts thereof can beprepared by or in analogy to the processes described hereafter.Accordingly, compounds of formula I and the salts thereof, can be forinstance obtained by a process as described here below.

[0098] A compound of formula I wherein G is as defined above and Q isdifferent from oxygen; X, B, A, R, R1 and R2 are as defined above can beobtained by reacting a compound of formula II

[0099] wherein B, X, A, R, R1 and R2 are as defined above, G₁ isrepresented by G, as defined above under a) to g) wherein Q is differentfrom oxygen and one or more nitrogens are protected with suitableprotective groups, such as, for instance, carbobenzyloxy ort-butoxycarbonyl, removable with a suitable reducing agent, or with anacid, such as trifluoroacetic acid or hydrochloric or hydrobromic acid.

[0100] A compound of formula II can be obtained by:

[0101] 1) reacting a compound of formula III

[0102] wherein G₁, X, B, R, R1 and R2 are as defined above and A is NH,with a suitable reducing agent, such as an alkali metal borohydride oran alkali metal cyanoborohydride thus obtaining a compound of formula IIwherein G₁, X, B, R, R1 and R2 are as defined above and A is NH. Acompound of formula III, wherein G₁, B, X, R, R1 and R2 are as definedabove and A is NH, can, in turn, be obtained by reacting a compound offormula IV

[0103] wherein G₁, B, X, and R1 are as defined above and A is NH₂, witha compound of formula V

[0104] wherein R and R2 are as defined above; or

[0105] 2) Reacting a compound of formula IV wherein G₁, B, X, and R1 areas defined above and A is SH, with a compound of formula VI

[0106] wherein R and R2 are as defined above, thus obtaining a compoundof formula II wherein G, X, B, R, R1 and R2 are as defined above, and Ais S; or

[0107] 3) Reacting compound of formula IV where G₁, B, X and R1 are asdefined above and A is OH with a compound of formula VII

[0108] wherein R and R2 are as defined above, and W is Cl, Br, I, OH orOSO₂C₁-C₄-alkyl or OSO₂Aryl, thus obtaining a compound of formula IIwherein G, X, B, R, R1 and R2 are as defined above, and A is O; or

[0109] 4) Reacting a compound of formula II, wherein G₁, X, B, R, R1 andR2 are as defined above, and A is S, with an oxydizing agent such asNalO₄, oxone, H₂O₂ or a peracid, thus obtaining a compound of formula IIwherein G₁, X, B, R1, R2 and R are as defined above and A is S(O)_(n)wherein n is 1 or 2, i.e. A is a sulfoxide or sulfone group; or

[0110] 5) Reacting a compound of formula VIII

[0111] wherein X, R, R1, R2 are as defined above, and A is CH₂, with acompound of formula IX

G₁—B—W  IX

[0112] wherein G₁, B and W are as defined above, thus obtaining acompound of formula II wherein G₁, X, B, R1, R2 and R are as definedabove and A is CH₂. A compound of formula VIII, as defined above, can,in turn, be obtained by reacting a compound of formula X

[0113] wherein X and R1 are as defined above, A is CH₂, W is selectedfrom Cl or Br and Z₁ is a suitable amide protecting group, such as ap-methoxy-benxyl group, with magnesium followed by addition of theresulting compound to a compound of formula VI, wherein R and R2 are asdescribed above, in the presence of suitable metal salts, like coppersalts, followed by removal of Z₁.

[0114] A compound of formula IV, as defined above wherein A is NH₂, canbe obtained by reduction of a compound of formula XI

[0115] wherein G₁, X, B and R1 are as defined above.

[0116] A compound of formula IV, wherein G₁, X, B and R1 are as definedabove and A is SH or OH can be obtained by a compound of formula XII

[0117] wherein, X, B and R1 are as defined above, A is S or O and Z₂ isa suitable protecting group for a —OH or a —SH moiety, such as methyl,p-methoxybenzyl, t-butyldimethylsilyl, p-nitrobenzyl, by removal of theZ₂ protecting group.

[0118] A compound of formula XI can be obtained by reacting a compoundof formula XIII

[0119] wherein X and R1 are as defined above, with a compound of formulaIX, as defined above.

[0120] A compound of formula XII can be obtained by reacting a compoundof formula XIV

[0121] wherein A, X, R1, and Z₂ are as defined above, with a compound offormula IX, as defined above.

[0122] A compound of formula I, wherein B, X, R, R1, R2 are as definedabove, A is CH₂, O or S, and G is as defined under a) wherein Q isoxygen, can be obtained by reacting a compound of formula XV

[0123] wherein B, X, R, R1, R2 are as defined above and A is CH₂, O orS, with an inorganic cyanate, such as sodium or potassium or ammoniumcyanate, or with an isocyanate of formula Q′NCO, wherein Q′ is asdescribed above.

[0124] A compound of formula I, wherein B, X, R, R1, R2 are as definedabove, A is CH₂, O or S, and G is as defined under a) wherein Q isdifferent from oxygen, or under b) and c), and Q′ is hydrogen, can beobtained by reacting a compound of formula XV with a suitableguanylating agent, such as, for instance,N,N′-di-t-butoxycarbonyl-N″-triflylguanidine or2-methylthio-2-imidazoline hydriodide or2-methylthio-1,4,5,6-tetrahydropyrimidine hydriodide, followed byremoval of the protecting groups in the case where the guanilating agentis N,N′-di-t-butoxycarbonyl-N″-triflylguanidine.

[0125] A compound of formula XV, as defined above, can be obtained byreaction of a compound of formula VIII, wherein X, R, R1, R2 are asdefined above, and A is CH₂, O or S, with a compound of formula XVI

Z₃—NH—B—W  XVI

[0126] wherein B and W are as defined above and Z₃ is a suitable aminoprotecting group such as, for instance, carbobenzyloxy ort-butoxycarbonyl, followed by removal of Z₃.

[0127] A compound of formula I, wherein B, X, R, R1, R2 are as definedabove, A is NH, and G is as defined under a) wherein Q is oxygen, can beobtained by reacting a compound of formula XVII

[0128] wherein B and R1 are as defined above, G is as defined under a)wherein Q is oxygen, and A is NH₂, with a compound of formula V,followed by reduction of the product with an alkali metal borohydride oran alkali metal cyanoboro-hydride. A compound of formula XVII, asdefined above, can be obtained in analogy to the procedures describedfor the synthesis of compounds of formula IV, provided that G, asdefined above, is substituted for G₁.

[0129] A compound of formula I, wherein B, X, R, R1, R2 are as definedabove, A is NH, and G is as defined under a) wherein Q is different fromoxygen, or under b) or c), and Q′ is hydrogen, can be obtained byreacting a compound of formula XV, wherein B, X, R, R1 and R2 are asdefined above, and A is NH, with a suitable guanilating agent, such as,for instance, N,N′-di-t-butoxy-carbonyl-N″-triflylguanidine or2-methylthio-2-imidazoline hydriodide or2-methylthio-1,4,5,6-tetrahydropyrimidine hydriodide, followed byremoval of the protecting groups in the case where the guanilating agentis N,N′-di-t-butoxy-carbonyl-N″-triflylguanidine.

[0130] A compound of formula XV, wherein B, X, R, R1 and R2 are asdefined above, and A is NH, in turn, can be obtained by reacting acompound of formula XIII, as defined above, with a compound of formulaXVI, as defined above, followed by: a) reduction of the nitro group, b)reaction with a compound of formula V, as defined above, c) reduction ofthe resulting compound with an alkali metal borohydride or an alkalimetal cianoborohydride, d) removal of the protectin group Z₃.

[0131] A compound of formula X or XIII or XIV, as defined above, can beprepared according to general methods described in the literature.

[0132] Additionally, a compound of formula I can be obtained by aprocess which comprises:

[0133] a) converting a compound of formula (I) into another compound offormula (I), or separating a single isomer of a compound of formula (I)from a mixture thereof, or converting a compound of formula (I) into asalt thereof, or converting a salt of a compound of formula (I) into afree compound of formula (I);

[0134] b) reacting a compound of formula I wherein G, X, B, A R1 and R2are as defined above and R is different from hydrogen with aqueous acidsor aqueous bases thus obtaining a compound of formula I wherein R ishydrogen;

[0135] The compounds described above can be prepared as exemplified inthe following procedures.

[0136] In a typical procedure, a compound of formula I, as definedabove, can be obtained by treatment of a compound of formula II, asdefined above, with hydrogen in the presence of a suitable catalyst,such as palladium on carbon, in a solvent like a lower alcohol ordioxane, or by treatment with trifluoroacetic acid or hydrobromic acidin acetic acid, followed by isolation of the product by chromatography.

[0137] In a typical procedure for the preparation of a compound offormula III, as defined above, a compound of formula IV, as definedabove, a keto-ester of formula V and anhydrous calcium sulfate andcatalytic acetic acid are mixed in an anhydrous alcohol, such asethanol, and refluxed for 24 to 96 hours. The compound is isolated bycolumn chromatography. The reduction of a compound of formula III withsodium cyanoborohydride in ethanol provides a compound of formula II, asdefined above and wherein A is NH.

[0138] In a typical procedure for the preparation of a compound offormula II, as defined above and wherein A is S, a compound of formulaIV, as defined above and wherein A is SH, is added to a solution of acompound of formula VI, as defined above, in a solvent liketetrahydrofuran or dichloromethane, in the presence of a small amount ofan organic base such as diazabicycloundecene (DBU). The reaction isallowed to proceed from 12 to 48 hours, at a temperature from about 20to about 40° C., and the product isolated by column chromatography.

[0139] In a typical procedure for the preparation of a compound offormula II, as defined above and wherein A is O, to a dichloromethane ortetrahydrofuran solution containing a compound of formula IV, as definedabove and wherein A is OH, triphenylphosphine and a compound of formulaVII, as defined above and wherein W is OH, a solution of an alkylazodicarboxylate in dichloromethane or tetrahydrofuran is added and themixture stirred at a temperature from room temperature to about 40° C.for 1 to 6 hours. The product is then isolated by column chromatography.The procedure described above is similar to procedures disclosed in theliterature (see, for instance, KRCHNAK, V., FLEGELOVA, Z., WEICHSEL, A.S., LEBL, M. Tetrahedron Letters 1995, 36, 6193-6196; or BROWN, R. F.C., JACKSON, W. R., McCARTHY, T. D. Tetrahedron 1994, 18, 5469-5488).

[0140] In a typical procedure for the preparation of a compound offormula II, as defined above and wherein A is SO₂, a compound of formulaII, as defined above and wherein A is S, is treated with 30% aqueousH₂O₂ in an alcohol as a solvent, or with NalO₄ in water and methanol, oracetone and water, (as described, for instance, in BEIER, C., SCHAUMANN,E. Synthesis 1997, 11, 1296-1300).

[0141] In a typical procedure for the preparation of a compound offormula II, as defined above and wherein A is SO, a compound of formulaII, as defined above and wherein A is S, is treated with oxone in amixture methanol/water as a solvent (as described, for instance, inHINTERBERGER, S., HOFER, O., GREGER, H. Tetrahedron 1998, 54, 487-496).

[0142] In a typical procedure for the preparation of a compound offormula II, as defined above and wherein A is CH₂, a Grignard reagentobtained from a compound of formula X, as defined above and wherein W isCl or Br and P1 is p-methoxybenzyl, is added to a mixture of cuprousiodide (Cul) and dry tetramethylene diamine (TMEDA) in drytetrahydrofuran at a temperature of about −78° C. The mixture is thenstirred at about −78° C. for between 15 minutes to 1 hours, then atetrahydrofuran solution of chlorotrimethyl silane and a compound offormula IV, as defined above, is added and the temperature allowed torise to about −30° C. After a period of 12 to 36 hours, the reaction istreated with a saturated aqueous solution of ammonium chloride andammonium hydroxide and extracted with a suitable solvent, such asdichloromethane, chloroform, diethylether, ethyl acetate and the productisolated by column chromatography (see, for instance, VAN HEERDEN, P.S., BEZUIDENHOUDT, B. C. B., FERREIRA, D. Tetrahedron 1996, 52,12313-12322; or VAN HEERDEN, P. S., BEZUIDENHOUDT, B. C. B., FERREIRA,D. J. Chem. Soc. Perk. Trans. 1, 1997, 1141-1146). Then, thep-methoxybenzyl group is removed by catalytic hydrogenolysis, using asupported metal catalyst, such as palladium on carbon in a solvent likemethanol or ethanol, to give a compound of formula VIII, as definedabove and wherein A is CH₂. A compound of formula VIII, as definedabove, is then reacted with a compound of formula IX, as defined aboveand wherein W is typically OSO₂CH₃, in the presence of an organic base,such as potassium hexamethyldisilazide in a solvent like tetrahydrofuranor dimethylformamide or mixtures thereof, at a temperature from roomtemperature to about 100° C. for 1 to 6 hours, the product isolated bycolumn chromatography thus giving a compound of formula II, as definedabove and wherein A is CH₂.

[0143] In typical procedure for the preparation of a compound of formulaIV, as defined above and wherein A is NH₂, a compound of formula XI, asdefined above, is reduced by treatment with a mixture of titaniumtetrachloride and tin dichloride in a solvent like tetrahydrofuran ordiisopropyl ether or diethyl ether, at a temperature from about 20 toabout 40° C. and under an atmosphere of an inert gas. A compound offormula XI, as defined above, can be obtained by treatment of a compoundof formula XIII, as defined above, with a compound of formula IX, asdefined above and wherein W is typically OSO₂CH₃, in the presence of anorganic base, such as potassium hexamethyldisilazide in a solvent liketetrahydrofuran or dimethylformamide or mixtures thereof, at atemperature from room temperature to about 100° C. for 1 to 6 hours, andthe product isolated by column chromatography.

[0144] In typical procedure for the preparation of a compound of formulaXII, as defined above and wherein A is O or S and Z₂ is a protectinggroup such as methyl, ethoxymethyl, p-methoxybenzyl,t-butyldimethylsilyl, t-butyldiphenylsilyl, p-nitrobenzyl or othersuitable protecting group (see: GREENE, T. W., WUTS, P. G. M. Protectivegroup in organic synthesis, Wiley, 1999), a compound of formula XIV, asdefined above, is reacted with a compound of formula IX, as definedabove and wherein W is typically OSO₂CH₃, in the presence of an organicbase, such as potassium hexamethyldisilazide in a solvent liketetrahydrofuran or dimethylformamide or mixtures thereof, at atemperature from room temperature to about 100° C. for 1 to 6 hours.

[0145] In typical procedure for the preparation of a compound of formulaI, wherein B, X, R, R1, R2 are as defined above, A is CH₂, O or S, and Gis as defined under a) wherein Q is oxygen and Q′ is hydrogen, acompound of formula XV, as defined above, is reacted with a cyanatesalt, as e.g. an ammonium or sodium or potassium salt, in solvent suchas acetic acid or water, at a temperature from about 50 to about 100°C., for 2 to 12 hours (see, as an example, Organic Synthesis vol. IV, p.49, 1963).

[0146] In typical procedure for the preparation of a compound of formulaI, wherein B, X, R, R1, R2 are as defined above, A is CH₂, O or S, and Gis as defined under a) wherein Q is oxygen and Q′ is different fromhydrogen, a compound of formula XV, as defined above, is reacted with anisocyanate of formula Q′NCO, wherein Q′ is as defined above, in asolvent like dichloromethane, acetonitrile, tetrahydrofuran, dioxane ortoluene, in the presence of triethylamine, at a temperature from roomtemperature to about 100° C. and for 4 to 24 hours. The resultingcompound is isolated by column chromatography.

[0147] In a typical procedure for the preparation of a compound offormula I, wherein B, X, R, R1, R2 are as defined above, A is CH₂, O orS, and G is as defined under a) wherein Q is different from oxygen, orunder b) and c), and Q′ is hydrogen, a compound of formula XV is treatedwith a suitable guanylating agent, likeN,N′-di-t-butoxycarbonyl-N″-triflylguanidine or2-methylthio-2-imidazoline hydriodide or2-methylthio-1,4,5,6-tetrahydropyrimidine hydriodid in a solvent likedichloromethane, tetrahydrofuran, dioxane or a lower alcohol, at atemperature from room temperature to reflux, for 24 to 72 hours,followed by evaporation of the solvent and isolation of the product bychromatography. In typical procedure for the preparation of a compoundof formula XV, as defined above, a compound of formula VIII, wherein X,R1, R2 are as defined above, R is different from hydrogen and A is CH₂,O or S, with a compound of formula XVI, as defined above and wherein Wis Br or OSO₂CH₃, in the presence of an organic base, such as potassiumhexamethyldisilazide in a solvent like tetrahydrofuran ordimethylformamide or mixtures thereof, at a temperature from roomtemperature to 100° C. for 1 to 6 hours. The resulting compound isisolated by column chromatography, and the protecting group Z₃ is thenremoved following the standard procedures described in the literature(see: GREENE, T. W., WUTS, P. G. M. Protective group in organicsynthesis, Wiley, 1999).

[0148] In typical procedure for the preparation of a compound of formulaI, wherein B, X, R, R1, R2 are as defined above, A is NH, G is asdefined under a) wherein Q is oxygen and Q′ is as defined above, acompound of formula XVII, as defined above, is mixed with a keto-esterof formula V in the presence of anhydrous calcium sulfate and catalyticacetic acid, in a solvent like an anhydrous alcohol, such as ethanol,and refluxed for 24 to 96 hours. The compound is isolated by columnchromatography, then is treated with sodium cyanoborohydride in ethanolthus giving a compound of formula I, as defined above. A compound offormula XVII, as defined above, can be obtained using the same proceduredescribed above for the synthesis of compounds of formula IV, providedthat G, as defined under a), is substituted for G₁, and wherein A isNH₂.

[0149] In typical procedure for the preparation of a compound of formulaI, wherein B, X, R, R1, R2 are as defined above, A is NH, G is asdefined under a) wherein Q is different from oxygen, or under b) or c),and Q′ is hydrogen, a compound of formula XV, wherein B, X, R, R1 and R2are as defined above, and A is NH is reacted with a suitable guanylatingagent, like N,N′-di-t-butoxycarbonyl-N″-triflylguanidine or2-methylthio-2-imidazoline hydriodide or2-methylthio-1,4,5,6-tetrahydropyrimidine hydriodid in a solvent likedichloromethane, tetrahydrofuran, dioxane or a lower alcohol, at atemperature from room temperature to reflux, for 24 to 72 hours,followed by evaporation of the solvent and isolation of the product bychromatography. In the case where the guanilating agent isN,N′-di-t-butoxycarbonyl-N″-triflylguanidine, the product is thentreated with trifluoroacetic acid, to remove the nitrogen protectinggroups, the trifluoroacetic acid is evaporated to afford the desiredcompound. A compound of formula XV, as defined above, can be obtainedusing the synthetic sequence described before and applying some of theexperimental procedures described before.

[0150] In a typical procedure, a compound of formula I, as defined aboveand wherein R is hydrogen, is obtained by treatment of a compound offormula I, as defined above and wherein R is different form hydrogen,with a mixture of an aqueous acid, like hydrochloric acid, and a loweralcohol or dioxane, at a temperature from room temperature to about 40°C., for 1 to 24 hours.

[0151] Alternatively, a compound of formula I, as defined above andwherein R is different form hydrogen, is treated with an aqueous base,like sodium or lithium or potassium hydroxide, in a solvent likemethanol or ethanol or dioxane, at a temperature from room temperatureto about 40° C., for 1 to 24 hours. The solution is then treated with anacid and the compound filtered.

[0152] A compound of formula X or XIII or XIV, as defined above, can beobtained according to general synthetic methods for 1,4-benzoxazines asdescribed, for instance, in METHODS OF ORGANIC CHEMISTRY (HOUBEN-WEIL),volume E 9a, pp. 141-177, George Thieme Verlag, Stuttgart 1997, or bysuitable modifications of such methods as known to those skilled in theart. Also the optional salification of a compound of formula (I) as wellas the conversion of a salt into the free compound and the separation ofa mixture of isomers into the single isomers may be carried our byconventional methods. For example, the separation of optical isomers maybe carried out by salification with an optically active base or acid andby subsequent fractional crystallisation of the diastereoisomeric salts,followed by recovering of the optically active isomeric acids or bases,respectively.

[0153] When in the compound of formula (I), and in the intermediateproducts thereof, groups are present which need to be protected beforesubmitting them to the here-above illustrated reactions, they may beprotected before the reactions take place and then deprotected,according to methods well known to those skilled in the art.

[0154] The compounds of formula (I) and the pharmaceutically acceptablesalts thereof are herein defined as the “compounds of the presentinvention”, the “compounds of the invention” and/or the “activeprinciples of the pharmaceutical compositions of the invention”.

[0155] The following examples describe the invention without limitingit.

EXAMPLE 1

[0156] The compounds of the Example 1 can be equally named as3-amino-3-phenylpropanoic acid derivatives or 3-phenyl-beta-alaninederivatives. The preparation of compounds3-{4-[3-(N-(2-pyridinyl)amino)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)amino}-3-phenylpropanoicacid,3-{4-[4-(N-(2-pyridinyl)amino)butyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)amino}-3-phenylpropanoicacid, and3-{4-[3-(N-(2-pyridinyl)amino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl)amino}-3-phenylpropanoicacid are provided. The aforementioned compounds can be synthesized asreported in Scheme 1.

[0157] The alkylating agents3-{[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]}-alkylmethanesulfonates have been prepared as described in Scheme 2.

[0158]3-{4-[3-(N-(2-Pyridinyl)Amino)Propyl]-3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl)Amino}-3-PhenylpropanoicAcid (orN-{3-Oxo-4-[3-(2-Pyridinylamino)-Propyl]-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl}-3-Phenyl-Beta-Alanine)(1a)

[0159] 7-Nitro-3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazine, 3

[0160] To a stirred solution of 2-amino-5-nitrophenol (10 g, 0.065 mol),triethylamine (13.79 g, 0.136 mol) and dimethylaminopyridine (0.16 g,0.0013 mol) in anhydrous dichloromethane (200 mL), at 0° C. and undernitrogen atmosphere, chloroacetylchloride (7.69 g, 0.068 mol) was added.The mixture was refluxed for 10 h, poured into aqueous sodium bisulfate,extracted with dichloromethane and the residue purified by flashchromatography (petroleum ether/ethyl acetate 1:1, then pure ethylacetate). The fraction containing the compound were evaporated, theresidue treated with diethylether and filtered to give 9.9 g (79%) ofthe title compound as a yellow solid.

[0161] 3-{[N-Benzyloxycarbonyl-N-(1-Oxido-2-Pyridinyl)Amino]}PropylMethanesulfonate, 11 (n=1)

[0162] 3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino] propanol wasprepared by reaction of 3-[N-(1-oxido-2-pyridinyl)amino] propanol(obtained as described in MILLER, W. H. et al. Bioorg. Med. Chem. Lett.1999, 9 1807-1812) with benzyl chloroformate according to the standardprocedure.

[0163] To a stirred solution of3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)-amino] propanol (3 g,9.92 mmol) and triethylamine (1.2 g, 11.91 mmol) in anhydrousdichloromethane, kept at 0° C. under nitrogen atmosphere,methanesulfonyl chloride (1.36 g, 11.91 mmol) was added, the reactionwas allowed to warm to room temperature and stirred for 1 h. The mixturewas washed with ice-water, dried with sodium sulfate, filtered andconcentrated to give 2.17 g (61%) of3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]-propylmethanesulfonate which, when required, was purified by flashchromatography (dichloromethane/methanol 95:5).

[0164]7-Nitro-4-{3-[N-Benzyloxycarbonyl-N-(1-Oxido-2-Pyridinyl)Amino]Propyl}-3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazine,4 (n=1)

[0165] To a stirred solution of 3 (1 g, 5.15 mmol) in THF/DMF 3:1 (15mL) cooled to 0° C. under nitrogen atmosphere, potassiumhexamethyidisilazide (1.33 g, 6.69 mmol) was added and the mixturestirred for 10 minutes. Then,3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]propylmethanesulfonate (2.0 g, 5.26 mmol) in THF was added in one portion, thereaction mixture heated at 80° C. for 3 hours, allowed to cool to roomtemperature and left standing overnight under a vigorous stirring. Thesolvent was removed, the residue taken up with water, extracted withdichloromethane, the organic fractions washed with aqueous sodiumbisulfate followed by sodium bicarbonate solution. After drying oversodium sulfate, the solvent was evaporated, the residue was purified byflash chromatography (dichloromethane/methanol 95:5) to give 0.83 g(34%) of the desired compound.

[0166]7-Amino-4-{3-[N-Benzyloxycarbonyl-N-(2-Pyridinyl)Amino]Propyl}-3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazine,5 (n=1)

[0167] In a round flask containing tetrahydrofuran under nitrogenatmosphere, were added titanium (IV) chloride (5 mL, 5.02 mmol) followedby stannous chloride dihydrate (1.2 g, 5.02 mmol). The mixture wasstirred 1 h at room temperature, then compound 4 (1 g, 2.1 mmol) wasadded. The mixture was heated 3 h to 40° C., stannous chloride dihydrate(1.2 g, 5.02 mmol) and ethanol (6 mL) were added and the mixture heatedfor further 3 h at 40° C. The solvent was evaporated, ice and aqueoussodium bicarbonate added, and the mixture extracted with ethyl acetate.The organic layers were combined, dried over sodium sulphate, thesolvent evaporated and the residue purified by flash chromatographyeluting with petroleum ether/ethyl acetate 1:1, yielding 0.63 g (70%) ofthe title compound as an oil.

[0168]¹H-NMR (400 MHz), δ (DMSO-d₆): 1.80 (m, 2H, CH₂), 3.78 (t, 2H,J=7.3, CH₂NCbz), 3.91 (t, 2H, J=7.3, —CH₂NCO), 4.42 (s, 2H, —CH₂O—),4.97 (s, 2H, NH₂), 5.14 (s, 2H, CH₂Ph), 6.20 (m, 2H, ArH), 6.73 (d, 1H,J=9, ArH), 7.17 (m, 1H, H-5 pyridine), 7.32 (m, 5H, PhH), 7.58 (m, 1H,H-3 pyridine), 7.77 (m, 1H, H-4 pyridine), 8.38 (m, 1H, H-6 pyridine).

[0169] Ethyl3-{4-[3-(N-Benzyloxycarbonyl-N-(2-Pyridinyl)Amino)propyl]-3-oxo-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl)Amino}-3-Phenylpropenoate,6 (n=1)

[0170] A mixture of 5 (n=1, 0.85 g, 1.96 mmol), ethyl benzoyl acetate(0.45 g, 2.36 mmol), anhydrous calcium sulfate (0.67 g, 4.91 mmol) andacetic acid (0.1 mL) in ethanol (20 mL) was refluxed for 80 h. Theinorganic salts were filtered, the solvent evaporated and the residuepurified by flash chromatography, eluting with petroleum ether/ethylacetate 1:1, to give 0.7 g (59%) of 6 (n=1).

[0171]¹H-NMR (400 MHz), δ (DMSO-d₆): 1.22 (t, 3H, J=7.1, CH₃CH₂OCO),1.80 (m, 2H, CH₂CH₂CH₂), 3.78 (t, 2H, J=7.3, CH₂NCbz), 3.88 (t, 2H,J=7.3, —CH₂NCO), 4.12 (q, 2H, J=7.1, CH₃CH₂OCO), 4.46 (s, 2H, —CH₂O—),4.90 (s, 1H, CH═CHCOO), 5.11 (s, 2H, CH₂Ph), 6.28 (dd, 1H, J=2.6, 8.8,ArH), 6.36 (d, 1H, J=2.6, ArH), 6.79 (d, 1H, J=8.8, ArH), 7.18 (m, 1H,H-5 pyridine), 7.30 (m, 10H, PhH), 7.57 (m, 1H, H-3 pyridine), 7.76 (m,1H, H-4 pyridine), 8.32 (m, 1H, H-6 pyridine), 10.06 (s, 1H, NH).

[0172] Ethyl3-{4-[3-(N-Benzyloxycarbonyl-N-(2-Pyridinyl)Amino)Propyl]-3-oxo-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl)Amino}-3-Phenylpropanoate,7 (n=1)

[0173] To a stirred solution of 6 (0.85 g, 1.4 mmol) and acetic acid (5mL) in ethanol (50 mL) under nitrogen atmosphere at 0° C., sodiumcyanoborohydride (0.44 g, 7.0 mmol) was added in one portion and thereaction allowed to warm to room temperature and stirred for 3h. Afterremoval of the solvent, the residue was dissolved in dichloromethane andthe organic phase washed with saturated sodium bicarbonate, dried,filtered and evaporated to give 0.74 g (88%) of 7 (n=1).

[0174]¹H-NMR (400 MHz), δ (DMSO-d₆): 1.10 (t, 3H, J=7.1, CH₃CH₂OCO),1.78 (m, 2H, CH₂CH₂CH₂), 2.72 (m, 2H, CLH COOEt), 3.75 (t, 2H, J=7.1,CH₂NCbz), 3.89 (t, 2H, J=7.1, —CH₂NCO), 4.00 (q, 2H, J=7.1, CH₃CH₂OCO),4.39 (s, 2H, —CH₂O—), 4.71 (m, 1H, PhCHNH), 5.10 (s, 2H, OCH₂Ph), 6.20(m, 3H, ArH+NH), 6.71 (d, 1H, J=9.5, ArH), 7.10-7.40 (m, 11H, PhH+H-5pyridine), 7.57 (m, 1H, H-3 pyridine), 7.75 (m,1H, H-4 pyridine), 8.32(m,1H, H-6 pyridine).

[0175] Ethyl3-{4-[3-(N-(2-Pyridinyl)Amino)Propyl]-3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl)Amino}-3-Phenylpropanoate,8 (n=1)

[0176] Compound 7 (0.75 g, 1.2 mmol) in acetic acid was cooled to 5-7°C., 30% hydrobromic acid in acetic acid (10 mL) was added and themixture stirred at room temperature overnight. The solvent was removed,the residue cooled and treated with saturated sodium bicarbonate at 5°C. The aqueous mixture was extracted with dichloromethane. The organicextracts were dried over sodium sulfate, evaporated to small volume andthe residue purified by flash chromatography (dichloromethane/methanol95:5) to give 0.3 g (50%) of 8 (m=1).

[0177]¹H-NMR (400 MHz), δ (DMSO-d₆): 1.10 (t, 3H, J=7.1, CH₃CH₂OCO),1.73 (m, 2H, CH₂CH CH₂), 2.73 (m, 2H, CH COOEt), 3.21 (m, 2H, CH₂NHPyr),3.81 (dd, 2H, J=7.1, 7.1, CH₂NCO), 4.01 (q, 2H, J=7.1, CH₃CH OCO), 4.44(s, 2H, —CH₂O—), 4.71 (m,1H, PhCHNH), 6.23 (m, 2H, 2ArH), 6.41 (m, 3H,NH+H-5 pyridine+H-3 pyridine), 6.81 (d, 1H, J=8.5, ArH), 7.20-7.40 (m,5H, PhH), 7.90 (m, 1H, H-6 pyridine).

[0178]3-{4-[3-(N-(2-Pyridinyl)Amino)Propyl]-3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl)Amino}-3-PhenylpropanoicAcid, 1a

[0179] To a stirred solution of 8 (m=1, 0.25 g, 0.53 mmol) in dioxane(12 mL) at 5° C., 2N sodium hydroxide (5 ml) was added and the mixturestirred overnight. The pH was adjusted to neutrality by adding thestoichiometric amount of 2N hydrochloric acid. Silica gel was added tothe mixture, the solvent was evaporated and the residue purified byflash chromatography (dichloromethane/methanol/acetic acid 85:15:1) togive 0.17 g (76%) of compound 1a as a white solid.

[0180] MS: m/z 447 (M+H⁺).

[0181]¹H-NMR (400 MHz), δ (DMSO-d₆): 1.71 (m, 2H, CH₂CHCH₂), 2.60 (m,2H, CH₂COOH), 3.20 (m, 2H, CH₂NHPyr), 3.80 (m, 2H, CH₂NCO), 4.43 (s, 2H,—CH₂O—), 4.67 (m,1H, PhCHNH), 6.19 (m, 2H, ArH), 6.25 (broad s, 1H, NH),6.40 (m, 3H, NH+H-5 pyridine+H-3 pyridine), 6.80 (d, 1H, J=8.5, ArH),7.18-7.40 (m, 6H, PhH+H-4 pyridine), 7.89 (m, 1H, H-6 pyridine).

[0182]3-{4-[4-(N-(2-Pyridinyl)Amino)Butyl]-3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl)Amino}-3-PhenylpropanoicAcid (or3-Phenyl-N-{4-[3-(2-Pyridinylamino)Butyl]-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl}-Beta-Alanine),1b.

[0183] Compound 1b has been synthesized as reported in Scheme 1 andfollowing the procedure described above for compound 1a. The alkylatingagent 4-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino] butylmethansulfonate 11 (n=2) has been prepared from the correspondingalcohol as described above. Intermediates 4 to 8 (n=2) and the finalcompound have been obtained with yields comparable to those of the lowerhomologue.

[0184]¹H-NMR (400 MHz), δ (DMSO-d₆): 1.50 (m, 4H, CH₂CH₂CH₂CH₂), 2.60(m, 2H, CH₂COOH), 3.19 (m, 2H, CH₂NHPyr), 3.75 (m, 2H, CH₂NCO), 4.42 (s,2H, CH₂O), 4.68 (m,1H, PhCHNH), 6.16 (d,1H, J=2.5, ArH), 6.20 (dd, 1H,J=2.5, 8.7, ArH), 6.30 (broad s, 1H, NH), 6.40 (m, 3H, NH+H-5pyridine+H-3 pyridine), 6.80 (d, 1H, J=8.7, ArH), 7.19 (m, 1H, H-4pyridine), 7.27-7.40 (m, 5H, PhH), 7.89 (m, 1H, H-6 pyridine).

[0185]3-{4-[3-(N-(2-Pyridinyl)Amino)Propyl]-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl)Amino}-3-PhenylpropanoicAcid (orN-{4-[3-(2-Pyridinylamino)propyl]-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl}-3-Phenyl-Beta-Alanine),2,

[0186] Compound 2 has been synthesized from 7 (n=1) as reported inScheme 1.

[0187] Ethyl3-{4-[3-(N-Benzyloxycarbonyl-N-(2-Pyridinyl)Amino)Propyl]-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl)Amino}-3-Phenylpropanoate,9

[0188] Compound 7 (m=1, 0.1 g, 0.16 mmol) was dissolved in THF, cooledand treated with 1M boron hydride-tetrahydrofuran complex (0.75 mL, 0.75mmol). The mixture was refluxed for 3 h, cooled, acidified with 0.5Nhydrochloric acid, poured into water and extracted with ethyl acetate.The organic extracts were washed with saturated sodium bicarbonate,dried over sodium sulfate and the solvent evaporated. The residue waspurified by flash chromatography, eluting with petroleum ether/ethylacetate 7:3, to give 0.063 g (65%) of 9 as a yellow oil.

[0189] Ethyl3-{4-[3-(N-(2-Pyridinyl)Amino)Propyl]-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl)Amino}-3-Phenylpropanoate,10

[0190] Compound 9 (0.06 g, 0.1 mmol) in acetic acid was cooled to 5-7°C., 30% hydrobromic acid in acetic acid (10 mL) was added and themixture stirred at room temperature overnight. The solvent was removed,the residue cooled and treated with saturated sodium bicarbonate at 5°C. The aqueous mixture was extracted with dichloromethane. The organicextracts were dried over sodium sulfate, evaporated to small volume andthe residue purified by flash chromatography (dichloromethane/methanol95:5) to give 0.028 g (61%) of 10.

[0191]3-{4-[3-(N-(2-Pyridinyl)Amino)Propyl]-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl)Amino}-3-PhenylpropanoicAcid, 2

[0192] To a stirred solution of 10 (0.025 g, 0.54 mmol) in dioxane (12mL) cooled to 5° C., 2N sodium hydroxide (5 mL) was added and themixture stirred overnight. The pH was adjusted to neutrality by addingthe stoichiometric amount of 2N hydrochloric acid. Silica gel was addedto the mixture, the solvent was evaporated and the residue purified byflash chromatography (dichloromethane/methanol/acetic acid 85:15:1) togive 0.017 g (76%) of PHA 513405 as a white solid.

[0193]¹H-NMR (400 MHz), δ (DMSO-d₆): 1.68 (m, 2H, CH₂CH₂CH₂), 2.58 (m,2H, CH₂COOH), 3.00-3.40 (m, 6H, CH₂NHPyr, 2 CH₂N), 4.03 (m, 2H, CH₂O),4.58 (m,1H, PhCHNH), 5.93 (d, 1H, J=2.4, ArH), 6.00 (dd, 1H, J=2.4, 8.6,ArH), 6.42 (m, 3H, ArH+H-5 pyridine+H-3 pyridine), 7.10-7.40 (m, 6H,PhH+H-4 pyridine), 7.91 (m, 1H, H-6 pyridine).

[0194] By analogous procedures the following compounds can be obtained:

[0195]3-phenyl-N-{4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine

[0196]3-phenyl-N-{4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine

[0197]N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine

[0198]N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine

[0199]N-{4-[2-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine

[0200]3-(3-pyridinyl)-N-{4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine

[0201]3-(3-pyridinyl)-N-{4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine

[0202]3-(3-pyridinyl)-N-{4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine

[0203]N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine

[0204]N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine

[0205]N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine

[0206]N-{3-oxo-4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine

[0207]N-{3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine

[0208]N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine

[0209]N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine

[0210]N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine

[0211]N-{3-oxo-4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine

[0212]N-{3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine

[0213]N-{3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine

[0214]N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine

[0215]N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine

[0216]N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine

[0217] either as a free acid or a salt thereof, in particular thehydrochloride or the trifluoroacetate.

EXAMPLE 2

[0218] The compound3-({3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoicacid can be prepared as described in Scheme 3.

[0219]3-({3-Oxo-4-[3-(2-Pyridinylamino)propyl]-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl}Oxy)-3-PhenylpropanoicAcid, 1c

[0220] The title compound can be prepared starting from7-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine 14 which, in turn, can beobtained as described, for instance, in EREZ, M. et al. J. Med. Chem.1978, 21, 982-984. According to standard procedures, the compound isthen transformed into the7-(dimethyl-t-bytylsilyl)oxy-3-oxo-3,4-dihydro-2H-benzoxazine 15.

[0221]7-(Dimethyl-t-Bytylsilyl)Oxy-4-{3-[N-Benzyloxycarbonyl-N-(1-Oxido-2-Pyridinyl)Amino]Propyl}-3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazine,13

[0222] To a stirred solution of 12 in tetrahydrofuran anddimethylforamide, cooled to 0° C. under nitrogen atmosphere, potassiumhexamethyidisilazide is added and the mixture stirred for 10-15 minutes.Then, a solution of3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]propylmethanesulfonate in tetrahydrofuran is added, the reaction mixtureheated at 80° C. for 3 to 5 hours. The solvent is removed, the residuetaken up with water, extracted with dichloromethane, the organicfractions washed with aqueous sodium bisulfate followed by sodiumbicarbonate solution. After drying over sodium sulfate, the solvent isevaporated and the product is isolated by flash chromatography.

[0223]7-Hydroxy-4-{3-[N-Benzyloxycarbonyl-N-(1-Oxido-2-Pyridinyl)Amino]-Propyl}-3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazine,14

[0224] To a solution of7-(dimethyl-t-bytylsilyl)oxy-4-{3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazinein tetrahydrofuran is added a solution of tetrabutylammonium fluoride intetrahydrofuran and the reaction mixture left standing overnight. Then,the solvent is evaporated, and the residue taken up with an aqueoussolution of hydrochloric acid, and extracted with dichloromethane. Theorganic phase is washed with a solution of sodium bicarbonate, then withbrine and dried over anhydrous sodium sulfate. Evaporation of thesolvent yields the title compound.

[0225] Ethyl3-({3-Oxo-4-[3-(N-Benzyloxycarbonyl-N-(1-Oxido-2-Pyridinyl)Amino]-Propyl-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl}Oxy)-3-Phenylpropanoate,15

[0226] To a solution of7-hydroxy-4-{3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazinein dichloromethane are added 5 equivalents of tripenylphosphine and 1.1equivalents of 3-hydroxy-3-phenyl propanoic acid ethyl ester. A solutionof 5 equivalents of diisopropyl azodicarboxylate in dichloromethane isadded dropwise at room temperature over 1 hour. The reaction mixture isstirred at room temperature for six hours, then the solvent isevaporated and the product isolated by column chromatography.

[0227] Ethyl3-({3-Oxo-4-[3-(N-Benzyloxycarbonyl-N-(2-Pyridinyl)Amino]Propyl-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl}Oxy)-3-Phenylpropanoate,16

[0228] To a solution of titanium (IV) chloride in tetrahydrofuran undernitrogen atmosphere, is added and equimolar amount of stannous chloridedihydrate, and the mixture is stirred 1 hour at room temperature. Then,a solution of ethyl 3-({3-oxo-4-[3-(N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]propyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoateis added and the mixture heated 3 hours at 40° C. After evaporation ofthe solvent, ice and aqueous sodium bicarbonate are added, the mixtureextracted with ethyl acetate, and the organic layers are combined anddried over sodium sulphate. The solvent is evaporated and the product isisolated by column chromatography.

[0229] Ethyl3-({3-Oxo-4-[3-(N-(2-Pyridinyl)Amino]Propyl-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl}Oxy)-3-Phenylpropanoate,17

[0230] A solution of ethyl3-({3-oxo-4-[3-(N-benzyloxycarbonyl-N-(2-pyridinyl)-amino]propyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenyl-propanoatein acetic acid is cooled with an ice bath, and a solution of 30%hydrobromic acid in acetic acid is added. The mixture is stirred at roomtemperature overnight. The solvent is removed under reduced pressure,the residue cooled and treated with saturated sodium bicarbonate. Theaqueous mixture is extracted with dichloromethane. The organic extractsare dried over sodium sulfate, evaporated to small volume and theproduct is purified by flash chromatography.

[0231]3-({3-Oxo-4-[3-(2-Pyridinylamino)propyl]-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl}Oxy)-3-PhenylpropanoicAcid, 1c

[0232] A solution of ethyl3-({3-oxo-4-[3-(N-(2-pyridinyl)aminopropyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoatein ethanol is treated with an equimolar amount of 1N sodium hydroxidesolution. The mixture is stirred at room temperature overnight. Then,the pH is brought to neutrality with 1N hydrochloric acid, the solventis evaporated and the residue is purified by filtration through a smallpad of silica gel, eluting with a mixture of dichloromethane, methanoland acetic acid.

[0233] By analogous procedures the following compounds can be obtained:

[0234]3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoicacid;

[0235]3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoicacid;

[0236]3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoicacid;

[0237]3-({3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoicacid;

[0238]3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoicacid;

[0239]3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoicacid;

[0240]3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(pyridinyl)propanoicacid;

EXAMPLE 3

[0241]3-({3-Oxo-4-[3-(2-Pyridinylamino)propyl]-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl}Sulfanyl)-3-PhenylpropanoicAcid,

[0242] The compound can be synthesized as described in Scheme 4.

[0243]7-Methylthio-4-{3-[N-Benzyloxycarbonyl-N-(1-Oxido-2-Pyridinyl)Amino]-Propyl}-3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazine,19

[0244] The synthesis is performed, as depicted in Scheme 4, according tothe procedure described for derivative 4, by condensing the commerciallyavailable, 2-amino-5-(methylthio)phenol with chloroacetyl chloride andsubsequently alkylating the benzoxazinone 18 with compound 11, usingpotassium hexamethyldisilazide as a base intetrahydrofura/dimethylformamide at 80° C., yielding compound 19.

[0245]7-Thio-4-{3-[N-Benzyloxycarbonyl-N-(1-Oxido-2-Pyridinyl)Amino]Propyl}-3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazine,20

[0246] The demethylation of the methylthio function is performed bytreatment of compound 19 with m-cloro-perbenzoic acid and trifluoroceticanhydride, according to a procedure described in the literature (YOUNG,R. N.; GAUTHIER, J. Y.; COOMBS, W.; Tetrahedron Lett., 1984, 25, 1753).

[0247] Ethyl3-[(4-{3-[N-Benzyloxycarbonyl-N-(1-Oxido-2-Pyridinyl)Amino]Propyl}-3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl)Sulfanyl]-3-Phenylpropanoate21

[0248] To a solution of7-thio-4-{3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)-amino]propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazinein dimethylformamide is added an equimolar amount of ethyltrans-cinnamate and a 0.05 equivalents of diazabicycloundecene (DBU).The reaction mixture is stirred at room temperature for 12 hours. Thesolvent is evaporated and the product is purified by flashchromatography.

[0249] Ethyl3-({3-Oxo-4-[3-(2-Pyridinylamino)propyl]-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl}Sulfanyl)-3-Phenylpropanoate,22

[0250] To a solution of titanium (IV) chloride in tetrahydrofuran undernitrogen atmosphere, is added and equimolar amount of stannous chloridedihydrate, and the mixture is stirred 1 hour at room temperature. Then,a solution of ethyl3-[(4-{3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfanyl]-3-phenylpropanoateis added and the mixture heated 3 hours at 40° C. After evaporation ofthe solvent, ice and aqueous sodium bicarbonate are added, the mixtureextracted with ethyl acetate, and the organic layers are combined anddried over sodium sulfate. The solvent is evaporated and ethyl3-[(4-{3-[N-benzyloxycarbonyl-N-(2-pyridinyl)amino]-propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfanyl]-3-phenylpropanoateis isolated by column chromatography. A solution of ethyl3-[(4-{3-[N-benzyloxycarbonyl-N-(2-pyridinyl)amino]-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)sulfanyl]-3-phenylpropanoatein acetic acid is treated with a solution of 30% hydrobromic acid inacetic acid at room temperature overnight. The solvent is evaporatedunder reduced pressure, and the residue is treated with a saturatedsodium bicarbonate solution. The aqueous mixture is extracted withdichloromethane. The organic extracts are dried over sodium sulfate,evaporated to small volume and the product is purified by flashchromatography

[0251]3-({3-Oxo-4-[3-(2-Pyridinylamino)propyl]-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl}Sulfanyl)-3-PhenylpropanoicAcid 1d.

[0252] A solution of ethyl3-({3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoatein ethanol is treated with an equimolar amount of 1N sodium hydroxidesolution. The mixture is stirred at room temperature overnight. Then,the pH is brought to neutrality with 1N hydrochloric acid, the solventis evaporated under reduced pressure and the residue is purified byfiltration through a small pad of silica gel, eluting with a mixture ofdichloromethane, methanol and acetic acid.

[0253] By analogous procedures the following compounds can be obtained:

[0254]3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoicacid;

[0255]3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoicacid;

[0256]3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoicacid;

[0257]3-({3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-ppyridinyl)propanoicacid;

[0258]3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoicacid;

[0259]3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoicacid;

[0260]3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoicacid;

EXAMPLE 4

[0261]4-{3-Oxo-4-[3-(Pyridin-2-Ylamino)-Propyl]-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl}-3-PhenylbutanoicAcid, 1e

[0262] The compound can be synthesised as described in Scheme 5.

[0263] Compound 23 is easily prepared by protection of the hydroxylgroup of 5-hydroxymethyl-2-(4-methoxybenzylamino) phenol, which, inturn, is prepared as described in YADAGIRI, B., LOWN, J. W. SyntheticCommunications 1990, 20, 175-181.

[0264]7-(Dimethyl-t-Butylsilyl)Oxymethyl-4-p-Methoxybenzyl-3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazine,24

[0265] To a stirred solution of5-(dimethyl-t-butylsilyl)oxymethyl-2-(4-methoxybenzylamino) phenol inanhydrous dichloromethane, triethylamine and dimethylaminopyridine at 0°C. and under nitrogen atmosphere, chloroacetyl-chloride is added. Themixture is refluxed for 10 h, poured into aqueous sodium bisulfate,extracted with dichloromethane and the product isolated by flashchromatography.

[0266]7-Bromomethyl-4-p-Methoxybenzyl-3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazine, 25

[0267] A solution of7-(dimethyl-t-butylsilyl)oxymethyl-4-p-methoxybenzyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazinein tetrahydrofuran is treated with a solution of tetrabutylammoniumfluoride in tetrahydrofuran and the reaction mixture left standingovernight. The solvent is evaporated, the residue is treated withaqueous hydrochloric acid and extracted with dichloromethane. Theorganic phase is washed with a solution of sodium bicarbonate, brine andthen dried on sodium sulfate. Evaporation of the solvent and filtrationthrough a small pad of silica gel yields the pure7-hydroxymethyl-4-p-methoxybenzyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine.To a solution of7-hydroxymethyl-4-p-methoxybenzyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazinein dichloromethane is added triphenylphosphine and carboniumtetrabromide. Then a solution of diethyl azodicarboxylate indichloromethane is added dropwise and the reaction mixture stirred atroom temperature for 6 hours. The solvent is evaporated and the productisolated by flash chromatography.

[0268] Ethyl4-[3-Oxo-4-[p-Methoxybenzyl]-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl]-3-Phenylbutanoate,26

[0269] To a suspension of Cul in dry tetrahydrofuran under argon areadded 1.1 equivalents of tetramethylene diamine and the reaction mixturestirred at room temperature for 15 minutes. The solution is cooled to−78° C. and the Grignard reagent prepared from7-bromomethyl-4-p-methoxybenzyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine isadded and the reaction mixture stirred for 15 minutes. Then, 2equivalents of trimethylsilyl chloride and a solution of ethyl cinnamatein tetrahydrofuran are added and the reactoin mixture is stirred whilethe temperature is allowed to rise to −30° C. After 18 hours thereaction is poured into a solution of ammonium chloride and ammoniumhydroxyde and extracted with dichloromethane. The extracts are washedwith water, dried over sodium sulfate, evaporated and the productisolated by flash chromatography.

[0270] Ethyl4-[3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazin-7-yl]-3-Phenylbutanoate, 27

[0271] To a solution of ethyl4-[3-oxo-4-[p-methoxybenzyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-3-phenylbutanoatein ethanol is added 10% Pd/C and the compound hydrogenated in a Parrapparatus. Evaporation of the solvent yields the title compound.

[0272] Ethyl3-[(4-{3-[N-Benzyloxycarbonyl-N-(1-Oxido-2-Pyridinyl)Amino]Propyl}-3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl)]-3-Phenylbutanoate,28

[0273] To a stirred solution of ethyl4-[3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]-3-phenylbutanoate intetrahydrofuran and dimethylforamide, cooled to 0° C. under nitrogenatmosphere, potassium hexamethyldisilazide is added and the mixturestirred for 10-15 minutes. Then, a solution of3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]propylmethanesulfonate in tetrahydrofuran is added, the reaction mixtureheated at 80° C. for 3 to 5 hours. The solvent is removed, the residuetaken up with water, extracted with dichloromethane, the organicfractions washed with aqueous sodium bisulfate followed by sodiumbicarbonate solution. After drying over sodium sulfate, the solvent wasevaporated and the product is isolated by flash chromatography.

[0274] Ethyl3-[(4-{3-[(2-Pyridinyl)Amino]Propyl}-3-Oxo-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl)]-3-Phenylbutanoate,29

[0275] To a solution of titanium (IV) chloride in tetrahydrofuran undernitrogen atmosphere, is added an equimolar amount of stannous chloridedihydrate, and the mixture is stirred 1 hour at room temperature. Then,a solution of ethyl3-[(4-{3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino]propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)]-3-phenylbutanoateis added and the mixture heated 3 hours at 40° C. After evaporation ofthe solvent, ice and aqueous sodium bicarbonate are added, the mixtureextracted with ethyl acetate, and the organic layers are combined anddried over sodium sulfate. The solvent is evaporated, the residue isdissolved in ethanol, 10% Pd/C is added and the compound hydrogenated ina Parr apparatus. The solvent is then evaporated and the product isisolated by column chromatography.

[0276]4-{3-Oxo-4-[3-(Pyridin-2-Ylamino)-Propyl]-3,4-Dihydro-2H-1,4-Benzoxazin-7-Yl}-3-PhenylbutanoicAcid, 1e

[0277] A solution of ethyl3-[(4-{3-[(2-pyridinyl)amino]propyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)]-3-phenylbutanoatein ethanol is treated with an equimolar amount of 1N sodium hydroxidesolution. The mixture is stirred at room temperature overnight. Then,the pH is brought to neutrality with 1N hydrochloric acid, the solventis evaporated under reduced pressure and the residue is purified byfiltration through a small pad of silica gel, eluting with a mixture ofdichloromethane, methanol and acetic acid.

[0278] By analogous procedures the following compounds can be obtained:

[0279]4-{3-oxo-4-[4-(pyridin-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoicacid;

[0280]4-{3-oxo-4-[3-(1H-imidazol-2-ylamino)-propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoicacid;

[0281]4-{3-oxo-4-[4-(1H-imidazol-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoicacid;

[0282]4-{3-oxo-4-[4-(pyridin-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoicacid;

[0283]4-(3-oxo-4-[3-(1H-imidazol-2-ylamino)-propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoicacid;

[0284]4-{3-oxo-4-[4-(1H-imidazol-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoicacid;

[0285] Pharmacology

[0286] The compounds of the invention are selective integrin receptorinhibitors or antagonists, and in particular they are inhibitors orantagonists of the α_(v)β₃ integrin receptor. The specific inhibiting orantagonist activity of the compounds of the invention is shown forinstance by the fact that they are active in in vitro solid phaseα_(v)β₃-vitronectin binding assay, as described below.

[0287] α_(v)β₃-Vitronectin Binding Assay

[0288] A solid phase assay for the study of α_(v)β₃-vitronectin bindingwas set up on the basis of already published methods (WONG et al.,Molecular Pharmacology 50: 529-537, 1996; Brooks et al., Cell 85:683-693, 1996). The human α_(v)β₃ integrin was diluted into coatingbuffer (CB) containing 150 mM NaCl, 1 mM CaCl₂, 1 mM MgCl₂, 1 mM MnCl₂,20 mM TRIS, pH 7.4 at a concentration of 1.5 μg/ml. Into 96-well plates,50 μl of the diluted integrin were added and allowed to bind to theplate walls overnight at 4° C. Next day, the assay plates were emptiedand 100 μl of blocking buffer (CB buffer with 3% BSA) were added to eachwell for 45 min at 37° C. After the incubation, the plates were washedthree times with 100 μl assay buffer (AB, CB buffer with 0.1% BSA);serial 1:1 dilution (25 μl/well) of the test compounds were added to theplates, starting from 10 mM solutions in 100% DMSO diluted to 100 μM inAB. The binding reaction was started by addition (25 μl/well) of 10 nMbiotinylated vitronectin (final concentration: 5 nM), and lasted 30 minat 37° C. The concentration range of the tested compounds spanned from50 to 0.0005 μM. At the end of the co-incubation, the assay plates werewashed as before and 70 μl of a 1:1000 AB dilution ofperoxydase-conjugated streptavidin were added per well and were allowedto react for 45 min at 37° C. Then, the plates were washed as describedand 50 μl of ready to use Turbo-TMB substrate for peroxydase were addedto each well. After 30 minutes incubation at room temperature, the colordevelopment was stopped with 50 μl sulphuric acid 0.38 M and the plateswere read at a wavelength of 450 nm with a Packard plate reader. Thevalues obtained were analyzed by four parameters curve fit in thecomputer program GraphPad Prism, after normalization by a maximumbinding control (Bmax) detected in wells where no competitor was added,and a minimum binding control (NSB) detected in wells where no integrinwas coated. Under standard assay conditions, A₄₅₀ was never under 1.0for Bmax, and around 0.15 for NSB. The computerized algorithm gave theconcentration of compound needed to inhibit the maximum binding by 50%(IC₅₀ value): for those compounds that did not inhibit this binding by50% at the highest concentration tested, IC₅₀ value was reported asbeing greater then the highest concentration tested. As a positivecontrol, increasing doses of a peptide containing the RGD sequence wasadded to each plate: IC₅₀ value of this molecule was 120 nM.

[0289] Materials

[0290] Human vitronectin receptor (α_(v)β₃) was purified from humanplacenta (PYTELA et al, Methods in Enzymology, 144: 475 -489, 1987).Turbo-TMB was from PIERCE (34022). BSA (A4503), Vitronectin (V8379), RGDpeptide (G4144) and all generic reagents were from SIGMA. Vitronectinwas biotinylated according to the procedure indicated in the NHSbiotinylation kit from PIERCE (21420). Horseradishperoxydase-streptavidin was from Amersham (RPN1231). 96-well plates werefrom Costar (#3690, EIA/RIA plate, ½ area flat bottom, high binding).

[0291] α_(IIb)β₃-Fibrinogen Binding Assay

[0292] A solid phase assay for the study of α_(IIb)β₃-fibrinogen bindingwas set up on according to the method described for α_(v)β₃. α_(IIb)β₃integrin was diluted into coating buffer (CB) containing 150 mM NaCl, 1mM CaCl₂, 1 mM MgCl₂, 1 mM MnCl₂, 20 mM TRIS, pH 7.4 at a concentrationof 3 □g/ml. Into 96-well plates, 50 μl of the diluted integrin wereadded and allowed to bind to the plate walls overnight at 4° C. Nextday, the assay plates were emptied and 100 μl of blocking buffer (CBbuffer with 3% BSA) were added to each well for 45 min at 37° C. Afterthe incubation, the plates were washed three times with 100 μl assaybuffer (AB, CB buffer with 0.1% BSA); serial 1:1 dilution (25 μl/well)of the test compounds were added to the plates, starting from 10 mMsolutions in 100% DMSO diluted to 100 □M in AB. The binding reaction wasstarted by addition (25 μl/well) of 20 nM biotinylated fibrinogen (finalconcentration: 10 nM), and lasted 30 min at 37° C. The concentrationrange of the tested compounds spanned from 50 to 0.0005 μM. At the endof the co-incubation, the assay plates were washed as before and 70 μlof a 1:1000 AB dilution of peroxydase-conjugated streptavidin were addedper well and were allowed to react for 45 min at 37° C. Then, the plateswere washed as described and 50 μl of ready to use Turbo-TMB substratefor peroxydase were added to each well. After 30 minutes incubation atroom temperature, the color development was stopped with 50 μl sulphuricacid 0.38 M and the plates were read at a wavelength of 450 nm with aPackard plate reader. The values obtained were analyzed by fourparameters curve fit with the computer program GraphPad Prism, afternormalization by a maximum binding control (Bmax) detected in wellswhere no competitor was added, and a minimum binding control (NSB)detected in wells where no integrin was coated. Under standard assayconditions, A₄₅₀ was never under 0.8 for Bmax, and around 0.15 for NSB.The computerized algorithm gave the concentration of compound needed toinhibit the maximum binding by 50% (IC₅₀ value): for those compoundsthat did not inhibit this binding by 50% at the highest concentrationtested, IC₅₀ value was reported as being greater then the highestconcentration tested. As a positive control, increasing doses of apeptide containing the RGD sequence was added to each plate: IC₅₀ valueof this molecule was 2.3 μM for α_(IIb)β₃-fibrinogen binding.

[0293] Materials

[0294] Human fibrinogen receptor ((α_(IIb)β₃) was purified from humanplatelets ((Pytela et al, Methods in Enzymology, 144: 475-489, 1987).Turbo-TMB was from PIERCE (34022). BSA (A4503), fibrinogen (F4883), RGDpeptide (G4144) and all generic reagents were from SIGMA. Fibrinogen wasbiotinylated according to the procedure indicated in the NHSbiotinylation kit from PIERCE (21420). Horseradishperoxydase-streptavidin was from Amersham (RPN1231). 96-well plates werefrom Costar (#3690, EIA/RIA plate, ½ area flat bottom, high binding).

[0295] For example, compoundN-{3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine,when tested in α_(v)β₃-vitronectin and α_(IIb)β₃-fibrinogen bidingassays, gave the following activity data:

α_(v)β₃ (IC ₅₀ μmol)=0.011±0.004

α_(IIb)β₃ (IC ₅₀ μmol)=18

[0296] These test data show that compoundN-{3-oxo-4-[3-(2-pyridinylamino)-propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanineacid is endowed with high selective α_(v)β₃ inhibiting activity. Infact, the ratio between α_(IIb)β₃ and α_(v)β₃ inhibiting activity isabout 1,000.

[0297] In view of their high selective aver inhibiting or antagonizingactivity, the compounds of the invention can be used in medicine intreating conditions mediated by the α_(v)β₃ integrin. Accordingly, thecompounds of the invention are useful for instance for treating variousconditions or disease states including osteoporosis, humoralhypercalcemia of malignancy, Paget's disease, tumor metastasis, solidtumor growth (neoplasia), angiogenesis including tumor angiogenesis,retinopathy including diabetic retinopathy, arthritis includingrheumatoid arthritis, psoriasis, periodontal disease, smooth muscle cellmigration and restenosis in a mammal in need of such treatment.Additionally, such pharmaceutical agents are useful as antiviral agents,and antimicrobials.

[0298] According to a preferred object of the invention the α_(v)β₃inhibiting activity results in an anticancer therapy having increasedeffectiveness in controlling, i.e., slowing, interrupting, arresting,stopping or reversing, the neoplasm formation.

[0299] The compounds of the invention can be administered in a varietyof dosage forms, e.g. orally, in the form of tablets, capsules, sugar-or film-coated tablets, liquid solutions or suspensions; rectally, inthe form of suppositories; parenterally, e.g. intramuscularly, or byintravenous injection of infusion; or topically.

[0300] The dosage regimen for the compounds and/or compositionscontaining the compounds is based on a variety of factors, including thetype, age, weight, sex and medical condition of the patent; the severityof the condition; the route of administration; and the activity of theparticular compound employed. Thus the dosage regime may vary widely.Dosage levels of the order from about 0.01 mg to about 1000 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions and more preferably of the order from about0.01 mg to about 100 mg/kg of body weight. For instance, the dosageadopted for oral administration to adult humans for compound PHA 509055may range from about 0.01 mg to about 800 mg/kg of body weight per dayand more preferably of the order from about 0.01 mg to about 750 mg/kgbody weight.

[0301] When given parenterally a suitable daily dose for instance forcompound PHA 509055 would typically be about 0.01 to 100 mg/kg bodyweight injected per day in multiple doses depending on the factorslisted above and more preferably from about 0.01 mg to about 10 mg/kgbody weight.

[0302] The invention includes pharmaceutical compositions comprising acompound of formula (I) or a pharmaceutically acceptable salt thereof inassociation with a pharmaceutically acceptable excipient (which can be acarrier or diluent).

[0303] The pharmaceutical compositions containing the compounds of theinvention are usually prepared following conventional methods and areadministered in a pharmaceutically suitable form.

[0304] For example, the solid oral forms may contain, together with theactive compound, diluents, e.g. lactose, dextrose, saccharose,cellulose, corn starch or potato starch; lubricants, e.g. silica, talc,stearic acid, magnesium or calcium stearate, and/or polyethyleneglycols; binding agents, e.g. starches, arabic gums, gelatin,methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone;disaggregating agents, e.g. a starch, alginic acid, alginates or sodiumstarch glycolate, effervescing mixtures; dyestuffs; sweeteners; wettingagents, such as lecithin, polysorbates, laurylsulphates; and, ingeneral, non-toxic and pharmacologically inactive substances used inpharmaceutical formulations. Said pharmaceutical preparations may bemanufactured in known manner, for example by means of mixing,granulating, tabletting, sugar-coating or film-coating processes.

[0305] The liquid dispersion for oral administration may be, e.g.,syrups, emulsions and suspensions.

[0306] The syrup may contain as carrier, for example, saccharose orsaccharose with glycerine and/or mannitol and/or sorbitol.

[0307] The suspensions and the emulsions may contain as carrier, forexample, a natural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose or polyvinyl alcohol.

[0308] The suspensions or solutions for intramuscular injections maycontain, together with the active compound, a pharmaceuticallyacceptable carrier, e.g. sterile water, olive oil, ethyl oleate,glycols, e.g. propylene glycol, and, if desired, a suitable amount oflidocaine hydrochloride.

[0309] The solutions for intravenous injections or infusion may containas carrier, for example, sterile water or, preferably, they may be inthe form of sterile aqueous, isotonic saline solutions.

[0310] The suppositories may contain, together with the active compound,a pharmaceutically acceptable carrier, e.g. cocoa-butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

[0311] Compositions for topical application, e.g. creams, lotions orpastes, can be prepared by admixing the active ingredient with aconventional oleaginous or emulsifying excipient.

[0312] The following formulation examples illustrate but do not limitthe invention.

EXAMPLE 1

[0313] Capsules, each dosed at 0.200 g and containing 20 mg of theactive substance can be prepared.

[0314] Composition for 500 capsules:

[0315]N-{3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-N-{3-oxo-4-3[3-(2-pyridinylamino)- 10 gpropyl]-3,4-dihydro-2H-1,4-benzoxazin- 7-yl}-3-phenyl-beta-alanineLactose 80 g Corn starch  5 g Magnesium stearate  5 g

[0316] This formulation is encapsulated in two-piece hard gelatincapsules and dosed at 0.200 g for each capsule.

EXAMPLE 2

[0317] Tablets, each weighing 0.150 g and containing 25 mg of the activesubstance, can be manufactured as follows.

[0318] Composition for 10,000 tablets:

[0319] 3-phenyl-N-{4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,43-phenly-N-{4-]3-(2-pyridinylamino) 250 g propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine Lactose 800 g Corn starch 415 g Talcpowder  30 g Magnesium stearate  5 g

[0320] The3-phenyl-N-{4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine,the lactose and half the corn starch are mixed; the mixture is thenforced through a sieve of 0.5 mm mesh size. Corn starch (10 g) issuspended in warm water (90 ml) and the resulting paste is used togranulate the powder. The granulate is dried, comminuted on a sieve of1.4 mm mesh size, then the remaining quantity of starch, talc andmagnesium stearate are added, carefully mixed and processed intotablets.

EXAMPLE 3

[0321] Intravenous infusion 1-10 mg/ml.

[0322] An intravenous infusion pharmaceutical preparation can bemanufactured by dissolving 50 mg ofN-{3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alaninein water for injection (1000 ml) and sealing glass ampoules of 1-10 ml.Prior to infusion, the obtained solution can be diluted according to thecommon practice, and stored and/or delivered in glass, polypropylene,polyolefin or polyethylene-lined equipment.

[0323] The compounds of the present invention can be administered eitheras single agents or, alternatively, in combination with known anticancertreatments such as radiation therapy or chemotherapy regimen incombination with cytostatic or cytotoxic agents, antibiotic-type agents,alkylating agents, anti-metabolite agents, hormonal agents,immunological agents, interferon-type agents, cyclooxygenase inhibitors(e.g. COX-2 inhibitors), metallomatrix-protease inhibitors, telomeraseinhibitors, tyrosine kinase inhibitors, anti-growth factor receptoragents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents,farnesyl transferase inhibitors, ras-raf signal transduction pathwayinhibitors, cell cycle inhibitors, other cdks inhibitors, tubulinbinding agents, topoisomerase I inhibitors, topoisomerase II inhibitors,and the like. As an example, the compounds of the invention can beadministered in combination with one or more chemotherapeutic agentssuch as, for instance, taxane, taxane derivatives, encapsulated taxanes,CPT-11, camptothecin derivatives, anthracycline glycosides, e.g.,doxorubicin, idarubicin, epirubicin, etoposide, navelbine, vinblastine,carboplatin, cisplatin, estramustine, celecoxib, parecoxib, rofecoxib,valecoxib, JTE 5222, Sugen SU-5416, Sugen SU-6668, Herceptin, and thelike, optionally within liposomal formulations thereof. If formulated asa fixed dose, such combination products employ the compounds of thisinvention within the dosage range described above and the otherpharmaceutically active agent within the approved dosage range.

[0324] Compounds of formula (I) may be used sequentially with knownanticancer agents when a combination formulation is inappropriate.

[0325] The object of the present invention is to provide the use of acompound of formula (I), as herein defined, or a pharmaceuticallyacceptable salt thereof, in the preparation of a medicament having□_(v)□₃ integrin inhibiting or antagonizing activity for controlling thegrowth of the neoplasm in a method additionally comprising theadministration of an antitumor agent.

[0326] The combination preparation according to the invention can alsoinclude combination packs or compositions in which the constituents areplaced side by side and can therefore be administered simultaneously,separately or sequentially to one and the same human being. Accordingly,the antineoplastic agent and a compound according to the presentinvention may be present within a single or distinct container means.

[0327] In the combined preparations, pharmaceutical compositions andmethods of treating, according to the present invention, theantineoplastic agent may comprise 1 to 4, preferably 1, 2 or 3,antineoplastic drugs, in particular a single antineoplastic drug.

[0328] As used herein, “controlling the growth” of the neoplasm refersto slowing, interrupting, arresting or stopping its growth and it doesnot necessarily indicate a total elimination of the neoplasm. It isbelieved that prolonging the survivability of a patient, beyond being asignificant advantageous effect in and of itself, also indicates thatthe condition is beneficially controlled to some extent.

[0329] The term “antineoplastic agent” is meant to comprise both asingle antineoplastic cytotoxic drug and “cocktails”, i.e. mixtures ofsuch drugs, according to the clinical practice.

[0330] As used herein, the term “effective antineoplastic amount” refersto an amount which is effective, upon single or multiple doseadministration to the patient, in controlling the growth of the neoplasmor in prolonging the survivability of the patient beyond that expectedin the absence of such treatment.

[0331] In effecting treatment of a patient afflicted with a diseasestate described above a compound of formula (I) of the invention can beadministered in any form or mode which makes the compound bioavailablein effective amounts, including oral and parenteral routes. For example,it can be administered orally, subcutaneously, intraperitoneally,intramuscularly, intravenously, transdermally, and the like. Oral orintramuscular administration is generally preferred. One skilled in theart of preparing formulations can readily select the proper form andmode of administration depending upon the particular circumstances,including the disease state to be treated, the stage of the disease, theform of administration of the selected cytotoxic agent and the manner ofco-administration selected.

[0332] The selected antineoplastic agent can be administered by theappropriate route and dosing schedule as is well known and accepted forthe particular agent. For example, epirubicin, doxorubicin, idarubicin,paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide and vinblastinecan be administered intravenously. Idarubicin and cyclophosphamide canalso be given orally.

1. A compound of the formula (I)

or a pharmaceutically acceptable salt, prodrug or ester thereof,wherein: G is selected from the group consisting of

wherein Q is NH or O and Q′ is H, C₁-C₆ alkyl, phenyl, orphenyl-C₁-C₄-alkyl;

wherein R′ and R″ are independently H or C₁-C₄ alkyl; B is(CH₂)_(m)(CH═CH)_(p)Y, wherein m=1,2,3, p=0,1, Y is CH₂ or CO. X is CH₂or C═O; R1 is selected from the group consisting of H, C₁-C₄ alkyl,C₁-C₄ alkoxy, OH, halogen, CF₃; A is CH₂, NH, O, S(O)_(n) wherein n iszero, 1 or 2, R2 is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl orC₅-C₇ monocyclic heteroaryl ring containing one to three heteroatomsselected from O, S, and N, unsubstituted or optionally substituted byone to three substituents independently selected from the groupconsisting of H, C₁-C₄ alkyl, C₁-C₄ alkoxy, OH, halogen, CF₃; R ishydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₄ alkynyl, aryl or aryl-C₁-C₄alkyl.
 2. A compound according to claim 1, wherein G is selected fromthe group consisting of

wherein Q is NH or O and Q′ is selected from the group consisting of H,C₁-C₆ alkyl, phenyl, and phenyl-C₁-C₄-alkyl;

B is (CH₂)_(q) where q is 2,3,4; R2 is a phenyl or pyridine ringunsubstituted or optionally substituted by one to three substituentsindependently selected from the group consisting of H, C₁-C₄ alkyl,C₁-C₄ alkoxy, OH, halogen, CF₃.
 3. A compound according to claim 2,wherein G is selected from the group consisting of


4. The compound as recited in claim 1 wherein the compound is selectedfrom the group consisting of3-phenyl-N-{4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;3-phenyl-N-{4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;3-phenyl-N-{4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{4-[2-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;3-(3-pyridinyl)-N-{4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;3-(3-pyridinyl)-N-{4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;3-(3-pyridinyl)-N-{4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;N-(4-[2-(1H-imidazol-2-ylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{3-oxo-4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{4-[3-(1H-imidazol-2-ylamino)propy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{3-oxo-4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoicacid;3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoicacid;3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoicacid;3-({3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoicacid;3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoicacid;3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoicacid;3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(pyridinyl)propanoicacid;3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoicacid;3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoicacid;3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoicacid;3-({3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-ppyridinyl)propanoicacid;3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoicacid;3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoicacid;3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoicacid;4-{3-oxo-4-[4-(pyridin-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoicacid;4-{3-oxo-4-[3-(1H-imidazol-2-ylamino)-propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoicacid;4-{3-oxo-4-[4-(1H-imidazol-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoicacid;4-{3-oxo-4-[4-(pyridin-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoicacid;4-{3-oxo-4-[3-(1H-imidazol-2-ylamino)-propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoicacid;4-{3-oxo-4-[4-(1H-imidazol-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoicacid; either as a single isomer or as a mixture thereof, and thepharmaceutically acceptable salts thereof.
 5. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor a pharmaceutically acceptable salt, prodrug or ester thereof havingthe formula (I):

wherein: G is selected from the group consisting of

wherein Q is NH or O and Q′ is H, C₁-C₆ alkyl, phenyl, orphenyl-C₁-C₄-alkyl;

wherein R′ and R″ are independently H or C₁-C₄ alkyl; B is(CH₂)_(m)(CH═CH)_(p)Y, wherein m=1,2,3, p=0,1, Y is CH₂ or CO, X is CH₂or C═O; R1 is selected from the group consisting of H, C₁-C₄ alkyl,C₁-C₄ alkoxy, OH, halogen, CF₃; A is CH₂, NH, O, S(O)_(n) wherein n iszero, 1 or 2, R2 is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl orC₅-C₇ monocyclic heteroaryl ring containing one to three heteroatomsselected from O, S, and N, unsubstituted or optionally substituted byone to three substituents independently selected from the groupconsisting of H, C₁-C₄ alkyl, C₁-C₄ alkoxy, OH, halogen, CF₃; R ishydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₄ alkynyl, aryl or aryl-C₁-C₄alkyl.
 6. A pharmaceutical composition of claim 2 wherein: G is selectedfrom the group consisting of

wherein Q is NH or O and Q′ is selected from the group consisting of H,C₁-C₆ alkyl, phenyl, and phenyl-C₁-C₄-alkyl;

B is (CH₂)_(q) where q is 2,3,4; R2 is a phenyl or pyridine ringunsubstituted or optionally substituted by one to three substituentsindependently selected from the group consisting of H, C₁-C₄ alkyl,C₁-C₄ alkoxy, OH, halogen, CF₃.
 7. A pharmaceutical composition of claim3 wherein: G is selected from the group consisting of


8. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound or a pharmaceutically acceptable salt, prodrug orester thereof as recited in claim 5 wherein the compound is selectedfrom the group consisting of3-phenyl-N-{4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine3-phenyl-N-{4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine3-phenyl-N-{4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanineN-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanineN-{4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{4-[2-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;3-(3-pyridinyl)-N-{4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;3-(3-pyridinyl)-N-{4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;3-(3-pyridinyl)-N-{4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{3-oxo-4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{4-[3-(1H-imidazol-2-ylamino)propy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{3-oxo-4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoicacid;3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoicacid;3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoicacid;3-({3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoicacid;3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoicacid;3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoicacid;3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(pyridinyl)propanoicacid;3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoicacid;3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoicacid;3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoicacid;3-({3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-ppyridinyl)propanoicacid;3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoicacid;3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoicacid;3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoicacid;4-{3-oxo-4-[4-(pyridin-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoicacid;4-{3-oxo-4-[3-(1H-imidazol-2-ylamino)-propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoicacid;4-{3-oxo-4-[4-(1H-imidazol-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoicacid;4-{3-oxo-4-[4-(pyridin-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoicacid;4-{3-oxo-4-[3-(1H-imidazol-2-ylamino)-propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoicacid;4-{3-oxo-4-[4-(1H-imidazol-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoicacid; either as a single isomer or as a mixture thereof, and thepharmaceutically acceptable salts thereof.
 9. A method for treating acondition mediated by the avows integrin in a mammal in need of suchtreatment, including a human, comprising administering to said mammal aneffective α_(v)β₃ inhibiting amount of a compound of formula (I)

wherein: G is selected from the group consisting of:

wherein Q is NH or O and Q′ is H, C₁-C₆ alkyl, phenyl, orphenyl-C₁-C₄-alkyl;

wherein R′ and R″ are independently H or C₁-C₄ alkyl; B is(CH₂)_(m)(CH═CH)_(p)Y, wherein m =1,2,3, p=0,1, Y is CH₂ or CO, X is CH₂or C═O; R1 is selected from the group consisting of H, C₁-C₄ alkyl,C₁-C₄ alkoxy, OH, halogen, CF₃; A is CH₂, NH, O, S(O), wherein n iszero, 1 or 2, R2 is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl orC₅-C₇ monocyclic heteroaryl ring containing one to three heteroatomsselected from O, S, and N, unsubstituted or optionally substituted byone to three substituents selected independently from H, C₁-C₄ alkyl,C₁-C₄ alkoxy, OH, halogen, CF₃; R is selected from the group consistingof hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₄ alkynyl, aryl oraryl-C₁-C₄ alkyl.
 10. The method of claim 9 wherein: G is selected fromthe group consisting of

wherein Q is NH or O and Q′ is selected from the group consisting of H,C₁-C₆ alkyl, phenyl, and phenyl-C₁-C₄-alkyl;

B is (CH₂)_(q) where q is 2,3,4 R2 is a phenyl or pyridine ringunsubstituted or optionally substituted by one to three substituentsindependently selected from the group consisting of H, C₁-C₄ alkyl,C₁-C₄ alkoxy, OH, halogen, CF₃.
 11. The method of claim 9 wherein: G isselected from the group consisting of


12. The method according to claim 9 wherein the compound is selectedfrom the group consisting of3-phenyl-N-{4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine3-phenyl-N-{4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine3-phenyl-N-{4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanineN-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanineN-{4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{4-[2-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;3-(3-pyridinyl)-N-{4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;3-(3-pyridinyl)-N-{4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;3-(3-pyridinyl)-N-{4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{3-oxo-4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{4-[3-(1H-imidazol-2-ylamino)propy]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;N-{3-oxo-4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoicacid;3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoicacid;3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoicacid;3-({3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoicacid;3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoicacid;3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoicacid;3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(pyridinyl)propanoicacid;3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoicacid;3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoicacid;3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoicacid;3-({3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-ppyridinyl)propanoicacid;3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoicacid;3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoicacid;3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoicacid;4-{3-oxo-4-[4-(pyridin-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoicacid;4-{3-oxo-4-[3-(1H-imidazol-2-ylamino)-propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoicacid;4-{3-oxo-4-[4-(1H-imidazol-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoicacid;4-{3-oxo-4-[4-(pyridin-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoicacid;4-{3-oxo-4-[3-(1H-imidazol-2-ylamino)-propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoicacid;4-{3-oxo-4-[4-(1H-imidazol-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoicacid; either as a single isomer or as a mixture thereof, and thepharmaceutically acceptable salts thereof.
 13. The method according toclaim 9, wherein the condition treated is bone resorption, osteoporosis,humoral hypercalcemia of malignancy, Paget's disease, tumor metastasis,neoplasia (solid tumor growth), angiogenesis including tumorangiogenesis, diabetic retinopathy, arthritis, psoriasis and periodontaldisease, or smooth muscle cell migration including restenosis.
 14. Themethod according to claim 12, wherein the condition treated is boneresorption, osteoporosis, humoral hypercalcemia of malignancy, Paget'sdisease, tumor metastasis, neoplasia (solid tumor growth), angiogenesisincluding tumor angiogenesis, diabetic retinopathy, arthritis, psoriasisand periodontal disease, or smooth muscle cell migration includingrestenosis.
 15. A combined method of treatment of cancer or ofcontrolling the growth of a neoplasm in a mammal suffering from cancer,including a human, said method comprising administering simultaneous,separately or sequentially, 1) a compound of formula (I) as defined inclaim 1 or a pharmaceutically acceptable salts thereof and 2) anadditional antitumor agent; in amounts and close enough together in timesufficient to produce a therapeutically useful effect.
 16. The methodaccording to claim 15, wherein the additional antitumor agent isselected from the group consisting of an antineoplastic topoisomerase IIinhibitor, an antineoplastic antimicrotubule agent, an antineoplasticalkylating agent, an antineoplastic antimetabolite and an antineoplastictopoisomerase I inhibitor.
 17. A product containing a compound offormula (I) as defined in claim 1 or a pharmaceutically acceptable saltthereof, and an effective antineoplastic amount of additional antitumoragent as a combined preparation for simultaneous, separate or sequentialuse in anti-cancer therapy.
 18. The product according to claim 17,wherein the additional antitumor agent is selected from anantineoplastic topoisomerase II inhibitor, an antineoplasticantimicrotubule agent, an antineoplastic alkylating agent, anantineoplastic antimetabolite and an antineoplastic topoisomerase Iinhibitor.